Volume 21, Issue 1 (January 2023)                   IJRM 2023, 21(1): 17-32 | Back to browse issues page

XML Persian Abstract Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Yunaini L, Pujianto D A. Various gene modification techniques to discover molecular targets for non-hormonal male contraceptives: A review. IJRM 2023; 21 (1) :17-32
URL: http://ijrm.ir/article-1-2404-en.html
Various gene modification techniques to discover molecular targets for non-hormonal male contraceptives: A review
Luluk Yunaini * 1, Dwi Ari Pujianto2
1- Doctoral Program of Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, Indonesia. Department of Medicine Biology, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, Indonesia. , luluk.yunaini@ui.ac.id
2- Departement of Medicine Biology Faculty of Medicine, Universitas Indonesia,
Abstract:   (630 Views)
The identification and characterization of relevant targets are necessary for developing nonhormonal male contraceptives. The molecules must demonstrate that they are necessary for reproduction. As a result, a sophisticated technique is required to identify the molecular targets for nonhormonal male contraceptives. Genetic modification (GM) techniques are one method that can be applied. This technique has been widely used to study gene function that effected male fertility and has resulted in the discovery of numerous nonhormonal male contraceptive target molecules. We examined GM techniques and approaches used to investigate genes involved in male fertility as potential targets for nonhormonal contraceptives. The discovery of nonhormonal contraceptive candidate molecules was increased by using GM techniques, especially the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 method. The discovery of candidate nonhormonal contraceptive molecules can be a wide-open research for the development of nonhormonal male contraceptives. Therefore, we are believing that one day nonhormonal male contraceptives will be released.
Keywords: Gene modification, Non-hormonal, Male contraceptive.
Full-Text [PDF 2040 kb]   (425 Downloads) |   |   Full-Text (HTML)  (50 Views)  
Type of Study: Review Article | Subject: Reproductive Andrology
References
1. Naz RK, Rowan Sh. Female contraception: Present and future perspectives. Curr Womens Health Rev 2009; 5: 167-175. [DOI:10.2174/157340409789007259]
2. Arifuzzaman S, Rahman MS, Pang M-G. Research update and opportunity of non-hormonal male contraception : Histone demethylase KDM5B-based targeting. Pharmacol Res 2019; 141: 1-20. [DOI:10.1016/j.phrs.2018.12.003] [PMID]
3. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med 2016; 374: 843-852. [DOI:10.1056/NEJMsa1506575] [PMID] [PMCID]
4. Sundaram A, Vaughan B, Kost K, Bankole A, Finer L, Singh S, et al. Contraceptive failure in the United States : Estimates from the 2006-2010. Perspect Sex Reprod Health 2017; 49: 7-16. [DOI:10.1363/psrh.12017] [PMID] [PMCID]
5. Eisenstein M. Stopping sperm as the sperm. Nature 2020; 588: S170-S171. [DOI:10.1038/d41586-020-03534-4] [PMID]
6. Long JE, Lee MS, Blithe DL. Update on novel hormonal and nonhormonal male contraceptive development. J Clin Endocrinol Metab 2021; 106: e2381-e2392. [DOI:10.1210/clinem/dgab034] [PMID] [PMCID]
7. Pujianto DA, Loanda E, Sari P, Midoen YH, Soeharso P. Sperm-associated antigen 11A is expressed exclusively in the principal cells of the mouse caput epididymis in an androgen-dependent manner. Reprod Biol Endocrinol 2013; 11: 59. [DOI:10.1186/1477-7827-11-59] [PMID] [PMCID]
8. Pujianto AD, Muliawati D, Dara M, Parisudha A, Hardiyanto L. Mouse defensin beta 20 (Defb20) is expressed specifically in the caput region of the epididymis and regulated by androgen and testicular factors. Reprod Biol 2020; 20: 536-540. [DOI:10.1016/j.repbio.2020.09.003] [PMID]
9. Browne JA, Leir SH, Yin S, Harris A. Transcriptional networks in the human epididymis. Andrology 2019; 7: 741-747. [DOI:10.1111/andr.12629] [PMID] [PMCID]
10. Pujianto DA, Permatasari S. Mouse CD52 is predominantly expressed in the cauda epididymis, regulated by androgen and lumicrine factors. J Hum Reprod Sci 2021; 14: 350-355. [DOI:10.4103/jhrs.jhrs_29_21] [PMID] [PMCID]
11. Jamsai D, O'Bryan MK. Mouse models in male fertility research. Asian J Androl 2011; 13: 139-151. [DOI:10.1038/aja.2010.101] [PMID] [PMCID]
12. Tamowski S, Aston KI, Carrell DT. The use of transgenic mouse models in the study of male infertility. Syst Biol Reprod Med 2010; 56: 260-273. [DOI:10.3109/19396368.2010.485244] [PMID]
13. Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, et al. Europe PMC funders group origins and functional impact of copy number variation in the human genome. Nature 2010; 464: 704-712. [DOI:10.1038/nature08516] [PMID] [PMCID]
14. Lampreht Tratar U, Horvat S, Cemazar M. Transgenic mouse models in cancer research. Front Oncol 2018; 8: 268. [DOI:10.3389/fonc.2018.00268] [PMID] [PMCID]
15. Takehashi M, Kanatsu-Shinohara M, Shinohara T. Generation of genetically modified animals using spermatogonial stem cells. Dev Growth Differ 2010; 52: 303-310. [DOI:10.1111/j.1440-169X.2009.01167.x] [PMID]
16. Horii T, Morita S, Kimura M, Terawaki N, Shibutani M, Hatada I. Efficient generation of conditional knockout mice via sequential introduction of lox sites. Sci Rep 2017; 7: 7891. [DOI:10.1038/s41598-017-08496-8] [PMID] [PMCID]
17. Kim H, Kim M, Im S-K, Fang S. Mouse Cre-LoxP system : General principles to determine tissue-specific roles of target genes. Lab Anim Res 2018; 34: 147-159. [DOI:10.5625/lar.2018.34.4.147] [PMID] [PMCID]
18. Andersson KB, Winer LH, Mork HK, Molkentin JD, Jaisser F. Tamoxifen administration routes and dosage for inducible Cre-mediated gene disruption in mouse hearts. Transgenic Res 2010; 19: 715-725. [DOI:10.1007/s11248-009-9342-4] [PMID]
19. Ye R, Wang QA, Tao C, Vishvanath L, Shao M, Mcdonald JG, et al. Impact of tamoxifen on adipocyte lineage tracing : Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase. Mol Metab 2015; 4: 771-778. [DOI:10.1016/j.molmet.2015.08.004] [PMID] [PMCID]
20. Cong L, Zhang F. Genome engineering using CRISPR-Cas9 system. Methods Mol Biol 2015; 1239: 197-217. [DOI:10.1007/978-1-4939-1862-1_10] [PMID]
21. Mou H, Kennedy Z, Anderson DG, Yin H, Xue W. Precision cancer mouse models through genome editing with CRISPR-Cas9. Genome Med 2015; 7: 53. [DOI:10.1186/s13073-015-0178-7] [PMID] [PMCID]
22. Zhang Ch, Zhou Y, Xie Sh, Yin Q, Tang Ch, Ni Z, et al. CRISPR/Cas9-mediated genome editing reveals the synergistic effects of β-defensin family members on sperm maturation in rat epididymis. FASEB J 2018; 32: 1354-1363. [DOI:10.1096/fj.201700936R] [PMID]
23. Quadros RM, Miura H, Harms DW, Akatsuka H, Sato T, Aida T. Easi-CRISPR: A robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Genome Biol 2017; 18: 92. [DOI:10.1186/s13059-017-1220-4] [PMID] [PMCID]
24. Sipila P, Bjorkgren I. Segment-specific regulation of epididymal gene expression. Reproduction 2016; 152: R91-R99. [DOI:10.1530/REP-15-0533] [PMID]
25. Zhou YS, Webb Sh, Lettice L, Tardif S, Kilanowski F, Tyrrell C, et al. Partial deletion of chromosome 8 b-defensin cluster confers sperm dysfunction and infertility in male mice. PLOS Genet 2013; 9: e1003826. [DOI:10.1371/journal.pgen.1003826] [PMID] [PMCID]
26. Sharan ShK, Pyle A, Coppola V, Babus J, Swaminathan S, Benedict J, et al. BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 2004; 131: 131-142. [DOI:10.1242/dev.00888] [PMID]
27. Carvajal G, Brukman NG, Weigel Muñoz M, Battistone MA, Guazzone VA, Ikawa M, et al. Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4. Sci Rep 2018; 8: 17531. [DOI:10.1038/s41598-018-35719-3] [PMID] [PMCID]
28. Carlson AE, Burnett LA, del Camino D, Quill TA, Hille B, Chong JA, et al. Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation. PLoS One 2009; 4: e6844. [DOI:10.1371/journal.pone.0006844] [PMID] [PMCID]
29. Hsia K-H, Millar MR, King S, Selfridge J, Redhead NJ, Melton DW, et al. DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development 2003; 130: 369-378. [DOI:10.1242/dev.00221] [PMID]
30. Sun F, Palmer K, Handel MA. Mutation of Eif4g3, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes. Development 2010; 137: 1699-1707. [DOI:10.1242/dev.043125] [PMID] [PMCID]
31. O'Rand MG, Hamil KG, Adevai T, Zelinski M. Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS One 2018; 13: e0195953. [DOI:10.1371/journal.pone.0195953] [PMID] [PMCID]
32. Imai H, Hakkaku N, Iwamoto R, Suzuki J, Suzuki T, Tajima Y, et al. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. J Biol Chem 2009; 284: 32522-32532. [DOI:10.1074/jbc.M109.016139] [PMID] [PMCID]
33. Crackower MA, Kolas NK, Noguchi J, Sarao R, Kaneko H, Kobayashi E, et al. Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis. Science 2003; 300: 1291-1295. [DOI:10.1126/science.1083022] [PMID] [PMCID]
34. Fujihara Y, Lu Y, Noda T, Oji A, Larasati T, Kojima-Kita K, et al. Spermatozoa lacking fertilization influencing membrane protein (FIMP) fail to fuse with oocytes in mice. Proc Natl Acad Sci U S A 2020; 117: 9393-9400. [DOI:10.1073/pnas.1917060117] [PMID] [PMCID]
35. Martianov I, Brancorsini S, Catena R, Gansmuller A, Kotaja N, Parvinen M, et al. Polar nuclear localization of H1T2, a histone H1 variant, required for spermatid elongation and DNA condensation during spermiogenesis. Proc Natl Acad Sci U S A 2005; 102: 2808-2813. [DOI:10.1073/pnas.0406060102] [PMID] [PMCID]
36. Crapster JA, Rack PG, Hellmann ZJ, Le AD, Adams ChM, Leib RD, et al. HIPK4 is essential for murine spermiogenesis. Elife 2020; 9: e50209. [DOI:10.7554/eLife.50209] [PMID] [PMCID]
37. Aydin H, Sultana A, Li Sh, Thavalingam A, Lee JE. Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex. Nature 2016; 534: 562-565. [DOI:10.1038/nature18595] [PMID] [PMCID]
38. Kawa S, Ito Ch, Toyama Y, Maekawa M, Tezuka T, Nakamura T, et al. Azoospermia in mice with targeted disruption of the Brek/Lmtk2 (brain-enriched kinase/lemur tyrosine kinase 2) gene. Proc Natl Acad Sci U S A 2006; 103: 19344-19349. [DOI:10.1073/pnas.0603603103] [PMID] [PMCID]
39. Yang J, Medvedev S, Yu J, Tang LC, Agno JE, Matzuk MM, et al. Absence of the DNA-/RNA-binding protein MSY2 results in male and female infertility. Proc Natl Acad Sci U S A 2005; 102: 5755-5760. [DOI:10.1073/pnas.0408718102] [PMID] [PMCID]
40. Tsuda M, Sasaoka Y, Kiso M, Abe K, Haraguchi S, Kobayashi S, et al. Conserved role of nanos proteins in germ cell development. Science 2003; 301: 1239-1241. [DOI:10.1126/science.1085222] [PMID]
41. Nayernia K, Vauti F, Meinhardt A, Cadenas C, Schweyer S, Meyer BI, et al. Inactivation of a testis-specific Lis1 transcript in mice prevents spermatid differentiation and causes male infertility. J Biol Chem 2003; 278: 48377-48385. [DOI:10.1074/jbc.M309583200] [PMID]
42. Xu H, Beasley MD, Warren WD, Van Der Horst GTJ, Mckay MJ. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev Cell 2005; 8: 949-961. [DOI:10.1016/j.devcel.2005.03.018] [PMID]
43. Zeng X-H, Navarro B, Xia X-M, Clapham DE, Lingle ChJ. Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. J Gen Physiol 2013; 142: 305-313. [DOI:10.1085/jgp.201311011] [PMID] [PMCID]
44. Kherraf Z-E, Christou‐Kent M, Karaouzene T, Amiri‐Yekta A, Martinez G, Vargas AS, et al. SPINK 2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. EMBO Mol Med 2017; 9: 1132-1149. [DOI:10.15252/emmm.201607461] [PMID] [PMCID]
45. Noda T, Lu Y, Fujihara Y, Oura S, Koyano T, Kobayashi S, et al. Sperm proteins SOF1, TMEM95, and SPACA6 are required for sperm-oocyte fusion in mice. Proc Natl Acad Sci U S A 2020; 117: 11493-11502. [DOI:10.1073/pnas.1922650117] [PMID] [PMCID]
46. Tanaka H, Iguchi N, Toyama Y, Kitamura K, Takahashi T, Kaseda K, et al. Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function. Mol Cell Biol 2004; 24: 7958-7964. [DOI:10.1128/MCB.24.18.7958-7964.2004] [PMID] [PMCID]
47. Xu B, Hao Zh, Jha KN, Zhang Zh, Urekar C, Digilio L, et al. Targeted deletion of Tssk1 and 2 causes male infertility due to haploinsuf fi ciency. Dev Biol 2008; 319: 211-222. [DOI:10.1016/j.ydbio.2008.03.047] [PMID] [PMCID]
48. Noda T, Sakurai N, Nozawa K, Kobayashi S, Devlin DJ, Matzuk MM, et al. Nine genes abundantly expressed in the epididymis are not essential for male fecundity in mice. Andrology 2019; 7: 644-653. [DOI:10.1111/andr.12621] [PMID] [PMCID]
49. Chung SSW, Wang X, Wolgemuth DJ. Prolonged oral administration of a pan-retinoic acid receptor antagonist inhibits spermatogenesis in mice with a rapid recovery and changes in the expression of influx and efflux transporters. Endocrinology 2016; 157: 1601-1612. [DOI:10.1210/en.2015-1675] [PMID] [PMCID]
50. Busada JT, Geyer CB. The role of retinoic acid (RA) in spermatogonial differentiation. Biol Reprod 2016; 94: 10. [DOI:10.1095/biolreprod.115.135145] [PMID] [PMCID]
51. Chen Y, Zhu J-Y, Hong KH, Mikles DC, Georg GI, Goldstein AS, et al. Structural basis of ALDH1A2 inhibition by irreversible and reversible small molecule inhibitors. ACS Chem Biol 2018; 13: 582-590. [DOI:10.1021/acschembio.7b00685] [PMID] [PMCID]
52. Al Noman MDA, Kyzer JL, Chung SSW, Wolgemuth DJ, Georg GI. Retinoic acid receptor antagonists for male contraception: Current status. Biol Reprod 2020; 103: 390-399. [DOI:10.1093/biolre/ioaa122] [PMID] [PMCID]
53. Hawkinson JE, Sinville R, Mudaliar D, Shetty J, Ward T, Herr JC, et al. Potent pyrimidine and pyrrolopyrimidine inhibitors of testis-specific serine/threonine kinase 2 (TSSK2). Chem Med Chem 2017; 12: 1857-1865. [DOI:10.1002/cmdc.201700503] [PMID] [PMCID]
54. Srivastav A, Changkija B, Sharan K, Nagar GK. Influence of antifertility agents dutasteride and nifedipine on Catsper gene level in epididymis during seperm maturation in BALB/c mice. Reproduction 2018; 155: 347-359. [DOI:10.1530/REP-17-0664] [PMID]
55. Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, et al. Small-molecule inhibition of BRDT for male contraception. Cell 2012; 150: 673-684. [DOI:10.1016/j.cell.2012.06.045] [PMID] [PMCID]
56. Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewsk AJ, Gee CT, et al. BET bromodomain inhibitors with one-step synthesis discovered from virtual screen. J Med Chem 2017; 6: 4805-4817. [DOI:10.1021/acs.jmedchem.6b01336] [PMID] [PMCID]
57. Chávez JC, Ferreira JJ, Butler A, De La Vega Beltrán JL, Treviño CL, Darszon A, et al. SLO3 K+ channels control calcium entry through CATSPER channels in sperm. J Biol Chem 2014; 289: 32266-32275. [DOI:10.1074/jbc.M114.607556] [PMID] [PMCID]
58. Rennhack A, Schiffer C, Brenker C, Fridman D, Nitao ET, Cheng YM, et al. A novel cross-species inhibitor to study the function of CatSper Ca2+ channels in sperm. Br J Pharmacol 2018; 175: 3144-3161. [DOI:10.1111/bph.14355] [PMID] [PMCID]
59. O'Rand MG, Widgren EE, Sivashanmugam P, Richardson RT, Hall SH, French FS, et al. Reversible immunocontraception in male monkeys immunized with eppin. Science 2004; 306: 1189-1190. [DOI:10.1126/science.1099743] [PMID]
60. O'Rand M, Silva EJR, Hamil KG. Non-hormonal male contraception: A review and development of an Eppin based contraceptive. Pharmacol Ther 2017; 157: 105-111. [DOI:10.1016/j.pharmthera.2015.11.004] [PMID] [PMCID]
61. D'Francisco F, Merlo M, Vercellini R, Blanco P, Barbeito C, Gobello C. Effect of the indenopyridine RTI-4587-073 (l) on feline testicle. Anim Reprod Sci 2019; 205: 10-17. [DOI:10.1016/j.anireprosci.2019.03.014] [PMID]
62. Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biol Reprod 2008; 78: 1127-1138. [DOI:10.1095/biolreprod.106.057810] [PMID]
63. Mok K-W, Mruk D, Lie PPY, Lui W-Y, Cheng CY. Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. Reproduction 2011; 141: 571-580. [DOI:10.1530/REP-10-0464] [PMID] [PMCID]
64. Kwon W, Park Y, Kim Y, You Y, Kim IC, Pang M. Vasopressin effectively suppresses male fertility. PLoS One 2013; 8: e54192. [DOI:10.1371/journal.pone.0054192] [PMID] [PMCID]
65. Lee JS, Kwon WS, Rahman MS, Yoon SJ, Park YJ, Pang MG. Actin-related protein 2/3 complex-based actin polymerization is critical for male fertility. Andrology 2015; 3: 937-946. [DOI:10.1111/andr.12076] [PMID]
66. Peralta-Aris RD, Vivenes CY, Camejo MI, Pinero S, Proverbio T, Martinez E, et al. ATPases, ion exchangers and human sperm motility. Reproduction 2015; 149: 475-484. [DOI:10.1530/REP-14-0471] [PMID]
67. Sanbe A, Tanaka Y, Fujiwara Y, Tsumura H, Yamauchi J, Cotecchia S, et al. Alpha1-adrenoceptors are required for normal male sexual function. Br J Pharmacol 2007; 152: 332-340. [DOI:10.1038/sj.bjp.0707366] [PMID] [PMCID]
68. Borges CS, Missassi G, Pacini ESA, Kiguti LRA, Sanabria M, Pupo S, et al. Slimmer or fertile? Pharmacological mechanisms involved in reduced sperm quality and fertility in rats exposed to the anorexigen sibutramine. Plos Med 2013; 8: e66091. [DOI:10.1371/journal.pone.0066091] [PMID] [PMCID]
69. Zhang H, Yu H, Wang X, Zheng W, Yang B, Pi J, et al. (S)-α-chlorohydrin inhibits protein tyrosine phosphorylation through blocking cyclic AMP-protein kinase a pathway in spermatozoa. PLoS One 2012; 7: e43004. [DOI:10.1371/journal.pone.0043004] [PMID] [PMCID]
70. Balbach M, Fushimi M, Huggins DJ, Steegborn C, Meinke PT, Levin LR, et al. Optimization of lead compounds into on-demand, nonhormonal contraceptives: Leveraging a public-private drug discovery institute collaboration. Biol Reprod 2020; 103: 176-182. [DOI:10.1093/biolre/ioaa052] [PMID] [PMCID]
71. Akbari A, Pipitone GB, Anvar Z, Jaafarinia M, Ferrari M, Carrera P, et al. ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria. Hum Reprod 2019; 34: 1155-1164. [DOI:10.1093/humrep/dez048] [PMID]
72. Shettya J, Sinvilleb R, Shumilinc IA, Minorc W, Zhanga J, Hawkinson JE, et al. Recombinant production of enzymatically active male contraceptive drug target hTSSK2-localization of the TSKS domain phosphorylated by TSSK2. Protein Expr Purif 2016; 121: 88-96. [DOI:10.1016/j.pep.2016.01.009] [PMID] [PMCID]
73. Zhang H, Su D, Yang Y, Zhang W, Liu Y, Bai G, et al. Some single-nucleotide polymorphisms of the TSSK2 gene may be associated with human spermatogenesis impairment. J Androl 2010; 31: 388-392. [DOI:10.2164/jandrol.109.008466] [PMID]
74. Salicioni AM, Gervasi MG, Sosnik J, Tourzani DA, Nayyab S, Caraballo DA, et al. Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception. Biol Reprod 2020; 103: 264-274. [DOI:10.1093/biolre/ioaa064] [PMID] [PMCID]
75. Conlon RA. Chapter 5 transgenic and gene targeted models of dementia. In: Dam PPDD, Van D. Animal models of dementia neuromethods. Germani: Springer Science; 2011. [DOI:10.1007/978-1-60761-898-0_5]
Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Designed & Developed by : Yektaweb